Cytokine Levels in Experimental Branch Retinal Vein Occlusion Treated With Either Bevacizumab or Triamcinolone Acetonide.

Purpose: To compare gene expression changes following branch retinal vein occlusion (BRVO) in the pig with and without bevacizumab (BEV) and triamcinolone acetonide (TA). Methods: Photothrombotic BRVOs were created in both eyes of four groups of nine pigs (2, 6, 10, and 20 days). In each group, six pigs received intravitreal injections of BEV in one eye and TA in the fellow eye, with three pigs serving as untreated BRVO controls. Three untreated pigs served as healthy controls. Expression of mRNA of vascular endothelial growth factor (VEGF), glial fibrillary acidic protein (GFAP), dystrophin (DMD), potassium inwardly rectifying channel subfamily J member 10 protein (Kir4.1, KCNJ10), aquaporin-4 (AQP4), stromal cell-derived factor-1α (CXCL12), interleukin-6 (IL6), interleukin-8 (IL8), monocyte chemoattractant protein-1 (CCL2), intercellular adhesion molecule 1 (ICAM1), and heat shock factor 1 (HSF1) were analyzed by quantitative reverse-transcription polymerase chain reaction. Retinal VEGF protein levels were characterized by immunohistochemistry. Results: In untreated eyes, BRVO significantly increased expression of GFAP, IL8, CCL2, ICAM1, HSF1, and AQP4. Expression of VEGF, KCNJ10, and CXCL12 was significantly reduced by 6 days post-BRVO, with expression recovering to healthy control levels by day 20. Treatment with BEV or TA significantly increased VEGF, DMD, and IL6 expression compared with untreated BRVO eyes and suppressed BRVO-induced CCL2 and AQP4 upregulation, as well as recovery of KCNJ10 expression, at 10 to 20 days post-BRVO. Conclusions: Inflammation and cellular osmohomeostasis rather than VEGF suppression appear to play important roles in BRVO-induced retinal neurodegeneration, enhanced in both BEV- and TA-treated retinas. Translational Relevance: Inner retinal neurodegeneration seen in this acute model of BRVO appears to be mediated by inflammation and alterations in osmohomeostasis rather than VEGF inhibition, which may have implications for more specific treatment modalities in the acute phase of BRVO.

Ocular biomarkers: useful incidental findings by deep learning algorithms in fundus photographs.

BACKGROUND/OBJECTIVES: Artificial intelligence can assist with ocular image analysis for screening and diagnosis, but it is not yet capable of autonomous full-spectrum screening. Hypothetically, false-positive results may have unrealized screening potential arising from signals persisting despite training and/or ambiguous signals such as from biomarker overlap or high comorbidity. The study aimed to explore the potential to detect clinically useful incidental ocular biomarkers by screening fundus photographs of hypertensive adults using diabetic deep learning algorithms. SUBJECTS/METHODS: Patients referred for treatment-resistant hypertension were imaged at a hospital unit in Perth, Australia, between 2016 and 2022. The same 45° colour fundus photograph selected for each of the 433 participants imaged was processed by three deep learning algorithms. Two expert retinal specialists graded all false-positive results for diabetic retinopathy in non-diabetic participants. RESULTS: Of the 29 non-diabetic participants misclassified as positive for diabetic retinopathy, 28 (97%) had clinically useful retinal biomarkers. The models designed to screen for fewer diseases captured more incidental disease. All three algorithms showed a positive correlation between severity of hypertensive retinopathy and misclassified diabetic retinopathy. CONCLUSIONS: The results suggest that diabetic deep learning models may be responsive to hypertensive and other clinically useful retinal biomarkers within an at-risk, hypertensive cohort. Observing that models trained for fewer diseases captured more incidental pathology increases confidence in signalling hypotheses aligned with using self-supervised learning to develop autonomous comprehensive screening. Meanwhile, non-referable and false-positive outputs of other deep learning screening models could be explored for immediate clinical use in other populations.

Benefits of a Laser Chorioretinal Anastomosis Plus Ranibizumab vs Ranibizumab Alone for Central Retinal Vein Occlusion: 4-Year Results.

PURPOSE: To evaluate what clinical gains can be achieved over conventional treatment with ranibizumab alone for central retinal vein occlusion (CRVO) when causal pathology is additionally addressed successfully with a laser-induced chorio-retinal anastomosis (L-CRA). DESIGN: Two-year extension of prospective, randomized controlled clinical trial. METHODS: A total of 58 patients with macular edema secondary to CRVO were randomized 1:1 to receive either an L-CRA (n = 29) or sham procedure (n = 29) at baseline and then monthly intravitreal ranibizumab 0.5 mg. Outcomes (best corrected visual acuity [BCVA], central subfield thickness [CST], injection requirements) were monitored in the monthly pro re nata (PRN) ranibizumab phase from months 7 to 48. RESULTS: Injection requirements for patients with a functioning L-CRA (24 of 29) during the monthly PRN period from 7 to 24 months were a mean (95% CI) of 2.18 (1.57, 2.78) injections compared to 7.07 (6.08, 8.06) (P < .0001) for control (ranibizumab alone). These decreased further over the next 2 years to 0.29 (0.14, 0.61) compared to 2.20 (1.68, 2.88) (P < .001) for the third year and 0.25 (0.11, 0.56) and 1.84 (1.34, 2.54) for the fourth year (P < .001). Mean BCVA was statistically different at all follow-up time points from month 7 through month 48 for the group with the functioning L-CRA compared to the control monotherapy group. This improved to 14.06 letters at month 48 (P = .009). There was no difference in CST between any of the groups over the 48 months of follow-up. CONCLUSION: For CRVO patients, addressing causal pathology in addition to conventional therapy improves BCVA and reduces injection requirements.

Inner Retinal Changes in Acute Experimental BRVO Treated With Bevacizumab or Triamcinolone Acetonide.

Purpose: Apoptosis is a key process in neural degeneration associated with retinal vascular diseases. Vascular endothelial growth factor (VEGF) antagonists, including bevacizumab, are used to treat macular edema in these diseases. As VEGF has a critical role in the preservation of retinal neuronal cells, this study investigates the effects of bevacizumab on neural damage in a pig model of branch retinal vein occlusion (BRVO) and compares it with triamcinolone acetonide (TA) which is reported to possess neuroprotective properties. Methods: Thirty-six pigs had a photothrombotic BRVO in both eyes. Six pigs were injected with bevacizumab in one eye and TA in the fellow eye, then they were sacrificed, the eyes enucleated, and retinas processed at 2, 6, 10, and 20 days, respectively, together with three pigs (six eyes) BRVO only and three normal pigs (six eyes). Neuronal degeneration (apoptosis) and associated inner retinal changes were determined by terminal deoxyynuclotidyl transferase dUTP nick-end labeling (TUNEL), histology, and immunohistochemistry for macrophages. Results: TUNEL labeling showed significantly higher apoptosis rates in the ganglion cell layer (GCL) and the inner nuclear layer (INL) in the bevacizumab-treated compared with the TA-treated retinas at 2, 10, and 20 day time points after occlusion (P < 0.05). Pyknotic cells were significantly higher in the GCL in bevacizumab-treated eyes at 6, 10, and 20 days and in the INL at 2 days compared to TA-treated retinas (P < 0.05). Macrophage infiltration was seen at all time points in both untreated and treated retinas with an absence of significance between bevacizumab- and TA-treated retinas (P > 0.05). Conclusions: Neurodegeneration in the BRVO acute phase is exacerbated by current standard treatments for BRVO. These results may have implications for the timing and treatment type. Translational Relevance: In the acute phase of BRVO, VEGF suppression with bevacizumab and to a lesser extent with triamcinolone exacerbates apoptosis in the inner retinal layers, which has implications for both the timing and choice of treatment.

Vessel Pulse Amplitude Mapping in Eyes With Central and Hemi Retinal Venous Occlusion.

Purpose: The purpose of this study was to describe vessel pulse amplitude characteristics in eyes with central retinal vein occlusion (CRVO), hemiretinal vein occlusion (HVO), normal eyes (N1 N1), and the unaffected contralateral eyes of CRVO and HVO eyes (N1 CRVO and N1 HVO), as well as the unaffected hemivessels of HVO eyes (N2 HVO). Methods: Ophthalmodynamometry estimates of blood column pulse amplitudes with modified photoplethysmography were timed against cardiac cycles. Harmonic analysis was performed on the vessel reflectance within 0.25 to 1 mm from the disc center to construct pulse amplitude maps. Linear mixed modeling was used to examine variable effects upon the log harmonic pulse amplitude. Results: One hundred seven eyes were examined. Normal eyes had the highest mean venous pulse amplitude (2.08 ± 0.48 log u). CRVO had the lowest (0.99 ± 0.45 log u, P < 0.0001), followed by HVO (1.23 ± 0.46 log u, P = 0.0002) and N2 HVO (1.30 ± 0.59 log u, P = 0.0005). N1 CRVO (1.76 ± 0.34 log u, P = 0.52) and N1 HVO (1.33 ± 0.37 log u, P = 0.0101) had no significantly different mean amplitudes compared to N1 N1. Arterial amplitudes were lower than venous (P < 0.01) and reduced with venous occlusion (P < 0.01). Pulse amplitude versus amplitude over distance decreased along the N1 N1 vessels, with increasing slopes observed with CRVO (P < 0.01). Conclusions: Pulse amplitude reduction and attenuation characteristics of arteries and veins in venous occlusion can be measured and are consistent with reduced vessel wall compliance and pulse wave transmission. Translational Relevance: Retinal vascular pulse amplitudes can be measured, revealing occlusion induced changes, suggesting a role in evaluating the severity and progression of venous occlusion.

IMPACT OF RETINAL FLUID-FREE MONTHS ON OUTCOMES IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Treatment Agnostic Analysis of the HAWK and HARRIER Studies.

PURPOSE: To assess the effect of the total number of fluid-free months after loading on visual and anatomical outcomes in neovascular age-related macular degeneration patients receiving anti-vascular endothelial growth factor therapy. METHODS: This post hoc analysis pooled patient-level data from the brolucizumab 6 mg (n = 718) and aflibercept 2 mg (n = 715) arms of the HAWK and HARRIER randomized clinical trials. Based on data from Weeks 12 to 96, patients were assigned to one of five categories based on fluid-free visits (FFVs; the total number of monthly visits at which they were observed to be without retinal fluid). Three definitions of "fluid-free" were explored based on the location of the fluid observed. RESULTS: Patients allocated to Categories 4 (15-21 FFV) and 5 (22 FFV, always dry) consistently had the best visual and anatomical outcomes at Week 96, whereas patients allocated to Categories 1 (0 FFV, never dry) and 2 (1-7 FFV) consistently had the worst visual and anatomical outcomes. Variability in retinal thickness over time was lowest in Categories 4 and 5. CONCLUSION: Absence of retinal fluid at more visits after loading has a positive association with visual and anatomic outcomes in neovascular age-related macular degeneration patients, regardless of fluid type.

Endothelial contraction of retinal veins.

We have previously reported that porcine retinal veins can be contracted by vasoactive factors such as endothelin-1, but it is still unknown which cells play the major role in such contraction responses. This study seeks to confirm whether retinal vein endothelial cells play a significant role in the endothelin-1 induced contraction of porcine retinal veins. This is a novel study which provides confirmation of the endothelial cells' ability to contract retinal veins using a live vessel preparation. Retinal veins were isolated from porcine retina and cannulated for perfusion. The vessels were exposed to extraluminal delivery of endothelin-1 (10-8 M) and change in vessel diameter recorded automatically every 2 s. A phase contrast objective lens was also used to capture images of the endothelial cell morphometries. The length, width, area, and perimeter were assessed. In addition, vein histology and immuno-labeling for contractile proteins was performed. With 10-8 M endothelin-1 contractions to 63.6% of baseline were seen. The polygonal shape of the endothelial cells under normal tone became spindle-like after contraction. The area, width, perimeter and length were significantly reduced by 54.8%, 48.1%, 28.5% and 10.5% respectively. Three contractile proteins, myosin, calponin and alpha-SMA were found in retinal vein endothelial cells. Retinal vein endothelial cells contain contractile proteins and can be contracted by endothelin-1 administration. Such contractile capability may be important in regulating retinal perfusion but could also be a factor in the pathogenesis of retinal vascular diseases such as retinal vein occlusion. As far as we are aware, this is the first study on living isolated veins to confirm that endothelial cells contribute to the endothelin-1 induced contraction.

Longitudinal Analysis of Functional and Structural Outcome Measures in PRPH2-Associated Retinal Dystrophy.

PURPOSE: To establish disease progression rates in total lesion size (TLS), decreased autofluorescence (DAF) area, total macular volume (TMV), and mean macular sensitivity (MMS) in PRPH2-associated retinal dystrophy. DESIGN: Single-center, retrospective chart review. PARTICIPANTS: Patients with heterozygous pathogenic or likely pathogenic PRPH2 variants. METHODS: Patients who underwent serial ultrawide-field (UWF) fundus autofluorescence (FAF), OCT, and Macular Integrity Assessment microperimetry with at least 1 year of follow-up were included. Linear correlation was performed in eyes of all patients to determine the rate of change over time. MAIN OUTCOME MEASURES: Outcome measures included changes in TLS, DAF area, TMV, and MMS. RESULTS: Twelve patients (mean age, 55) from 10 unrelated families attended 100 clinic visits, which spanned over a mean (SD) of 4.7 (2.0) years. Mean (SD) TLS and DAF radius expansion were 0.14 (0.12) and 0.10 (0.08) mm/year, respectively. Mean (SD) TMV change was -0.071 (0.040) mm3/year with no interocular difference (P = 0.20) and strong interocular correlation (r2 = 0.88, P < 0.01). Mean (SD) MMS change was -0.10 (1.25) dB/year. Mean macular sensitivity declined in 4 and improved in 6 patients. Mean macular sensitivity was subnormal despite a TMV within the normal range. CONCLUSIONS: Serial measurements of UWF-FAF-derived TLS and DAF showed slow expansion. Total macular volume might be a more sensitive measure than MMS in detecting disease progression.

Five-year outcomes of eyes initially enrolled in the 2-year BEVORDEX trial of bevacizumab or dexamethasone implants for diabetic macular oedema.

BACKGROUND: The BEVORDEX trial compared outcomes of eyes with diabetic macular oedema (DMO) randomised to receive either intravitreal dexamethasone (DEX-) implant or bevacizumab over 2 years. We assessed long-term efficacy and safety outcomes 5 years from enrolment. METHODS: Patients received standard clinical care after they finished the study. Their files were reviewed for visual and anatomical outcomes, post-trial treatments and complications. RESULTS: Three-year and five-year data were available for 82% and 59% of eyes enrolled in the BEVORDEX study, respectively. Visual acuity gains at end of trial were generally lost by both treatment groups at 5 years but the macular thickness did not change from end of trial to 5 years. A similar proportion of eyes from each treatment group gained ≥10 letters at 5 years from enrolment in the BEVORDEX trial.Eyes that were initially randomised to the DEX-implant group had significantly fewer treatments but were more likely to develop proliferative diabetic retinopathy (PDR) over the 5-year period compared with eyes initially randomised to bevacizumab. The proportion of eyes that had cataract surgery by 5 years was similar between initial treatment groups. CONCLUSIONS: Eyes in the BEVORDEX trial had similar 5-year rates of cataract surgery, however, more eyes converted to PDR in the group initially treated with DEX-implant. Eyes that were initially treated for 2 years with either intravitreal DEX-implant of bevacizumab followed by standard of care had similar visual and anatomical outcomes at 5 years.

Central Retinal Vein Occlusion 36-Month Outcomes with Anti-VEGF: The Fight Retinal Blindness! Registry.

PURPOSE: To analyze the 3-year outcomes in a broad population of patients starting VEGF inhibitors for central retinal vein occlusion (CRVO) in routine clinical practice. DESIGN: Observational database study. PARTICIPANTS: Overall, 527 treatment-naïve CRVO eyes that commenced VEGF inhibitors between December 1, 2010 and 2018 were tracked in the Fight Retinal Blindness! registry. METHODS: Longitudinal models were used to plot changes in visual acuity (VA) and central subfield thickness (CST). MAIN OUTCOME MEASURES: Mean change in VA from baseline to 36 months, injections, visits, completion, switching, and suspensions of therapy > 180 days at the final review. RESULTS: Overall (527 eyes) mean VA change (95% confidence interval [CI]) was + 10 (7, 12) letters, 37% had final VA ≥ 70 and 30% ≤ 35 letters, mean CST changed -306 µm. Completers (257/527, 49%) had mean 36-month changes in VA and CST of + 12 letters and -324 µm with a median of 18 injections at 26 visits. The adjusted mean VA change was similar to each VEGF inhibitor (mean, + 11.4 letters) despite a greater reduction in CST with aflibercept (-310 µm) versus ranibizumab (-258 µm) versus bevacizumab (-216 µm; P < 0.001). Eyes with baseline VA that was trial-eligible (19-73 letters; 356/527, 68%) gained 7 letters, very poor (< 19 letters; 129/527, 24%) gained 22 letters, or very good (> 73 letters; 42/527, 8%) lost 7 letters. Switching (160/527, 30%) was most often to aflibercept (79 eyes). By using suspensions and discontinuation reasons, we identified similar proportions had ceased therapy (154/527, 29%) and were still receiving it at 36 months (165/527, 31%). Only 62/527 eyes (12%) had resolution of macular edema without treatment for > 6 months. CONCLUSIONS: Patients with CRVO that commenced VEGF inhibitors in routine care for whom follow-up was available had VA improvements of around 12 letters at 3 years, but with > 50% lost to follow-up, the VA outcome for the entire group was likely worse. The choice of VEGF inhibitor influenced CST but not VA outcomes. We estimated that around half of the eyes were still receiving injections after 36 months. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Hemiretinal vein occlusion 12-month outcomes are unique with vascular endothelial growth factor inhibitors: data from the Fight Retinal Blindness! Registry.

BACKGROUND/AIMS: To describe baseline characteristics and 12-month outcomes with vascular endothelial growth factor (VEGF) inhibitors of treatment-naïve hemiretinal vein occlusion (HRVO) compared with branch (BRVO) and central (CRVO) variants in routine clinical care. METHODS: A database observational study recruited 79 HRVO eyes, 590 BRVO eyes and 344 CRVO eyes that initiated therapy over 10 years. The primary outcome was mean change in visual acuity (VA-letters read on a logarithm of minimal angle of resolution chart) at 12 months. Secondary outcomes included mean change in central subfield thickness (CST), injections and visits. RESULTS: At baseline, mean VA in HRVO (53.8) was similar to CRVO (51.9; p=0.40) but lower than BRVO (59.4; p=0.009). HRVO eyes improved to match BRVO eyes from soon after treatment started through 12 months. Mean change in VA was greater in HRVO (+16.4) than both BRVO (+11.4; p=0.006) and CRVO (+8.5; p<0.001). Mean change in CST in HRVO (-231 µm) was similar to CRVO (-259 µm; p=0.33) but greater than BRVO eyes (-151 µm; p=0.003). The groups had similar median burdens of eight injections and nine visits. CONCLUSIONS: HRVO generally experienced the greatest mean change in VA of the three types of RVO when treated with VEGF inhibitors, ending with similar 12-month VA and CST to BRVO despite starting closer to CRVO. Inclusion of HRVO in BRVO or CRVO cohorts of clinical trials would be expected to proportionally inflate and skew the visual and anatomic outcomes.

Changes in 12-month outcomes over time for age-related macular degeneration, diabetic macular oedema and retinal vein occlusion.

OBJECTIVES: To identify whether the outcomes of neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO) in routine clinical practice have changed over time. METHODS: We analysed 12-month outcomes in treatment-naïve eyes that started aflibercept or ranibizumab for nAMD (3802 eyes), DMO (975 eyes), Branch RVO (BRVO, 357 eyes), Central RVO (CRVO, 371 eyes) and Hemi-RVO (HRVO, 54 eyes) from 2015 and 2019 tracked in the prospectively designed observational Fight Retinal Blindness! Registry. RESULTS: The mean VA change at 12-month for each year between 2015 and 2019 remained stable or otherwise showed no discernible trends over time in eyes with nAMD (+3.3 to +6 letters), DMO (+3.6 to +6.7 letters) and RVO (+10.3 to +11.7 letters for BRVO, +5.9 to +17.7 letters for CRVO and 10.2 to 20.7 letters for HRVO). The median number of VEGF-inhibitor injections in eyes that completed 12-month follow-up also remained stable at 8-9 for nAMD, 6-7 for DMO, 7-9 for RVO. Fewer eyes (

SIBLING CONCORDANCE IN SYMPTOM ONSET AND ATROPHY GROWTH RATES IN STARGARDT DISEASE USING ULTRA-WIDEFIELD FUNDUS AUTOFLUORESCENCE.

PURPOSE: To investigate concordance in symptom onset, area of dark autofluorescence (DAF), and growth rate (GR) between Stargardt disease siblings at an age-matched time point. METHODS: In this retrospective longitudinal study of sibling pairs with identical biallelic ABCA4 variants, age at symptom onset, best-corrected visual acuity, atrophy area, and effective radius of DAF on ultra-widefield fundus autofluorescence were recorded. Absolute intersibling differences for both eyes were compared with absolute interocular differences using the Mann-Whitney test. RESULTS: Overall 39 patients from 19 families were recruited. In 16 families, age-matched best-corrected visual acuity and DAF were compared between siblings. In 8 families, DAF GR was compared. The median (range) absolute difference in age at symptom onset between siblings was 3 (0-35) years. Absolute intersibling differences in age-matched best-corrected visual acuity were greater than interocular differences ( P = 0.01). Similarly, absolute intersibling differences in DAF area and radius were greater than interocular differences ( P = 0.04 for area and P = 0.001 for radius). Differences between absolute interocular and intersibling GR were not statistically significant ( P = 0.44 for area GR and P = 0.61 for radius GR). CONCLUSION: There was significant discordance in age-matched best-corrected visual acuity and DAF beyond the expected limits of interocular asymmetry. Lack of significant intersibling differences in GR warrants further investigation.

12-month outcomes of ranibizumab versus aflibercept for macular oedema in central retinal vein occlusion: data from the FRB! registry.

PURPOSE: To compare 12-month treatment outcomes of eyes receiving aflibercept or ranibizumab for macular oedema secondary to central retinal vein occlusion (CRVO) in routine clinical practice. METHODS: 296 treatment-naïve eyes receiving either aflibercept (171 eyes, 2 mg) or ranibizumab (125 eyes, 0.5 mg) for macular oedema secondary to CRVO were recruited retrospectively from centres using the prospectively designed FRB! registry. The primary outcome measure was the mean change in LogMAR letter scores of visual acuity (VA). Secondary outcomes included change in central subfield thickness (CST), injections and visits, time to first grading of inactivity, switching and non-completion from baseline to 12 months. RESULTS: Baseline VA (SD) was somewhat better in aflibercept- versus ranibizumab-treated eyes (42.5 ± 25.5 letters versus 36.9 ± 26 letters; p = 0.07) with similar CST (614 (240) µm versus 616 (234) µm: p = 0.95). The 12-month adjusted mean (95%CI) VA change was +16.6 (12.9, 20.4) letters for aflibercept versus +9.8 (5.5, 14.1) letters for ranibizumab (p = 0.001). The mean (95%CI) adjusted change in CST was significantly greater in aflibercept- versus ranibizumab-treated eyes: -304 (-276, -333) µm versus -252 (-220, -282) µm (p < 0.001). Both groups had a median (Q1, Q3) of 7 (5, 9) injections and 10 (8,13) visits. Aflibercept-treated eyes became inactive sooner than ranibizumab (p = 0.02). Switching occurred more commonly from ranibizumab (26 eyes, 21%) than from aflibercept (9 eyes, 5%) (p < 0.001). CONCLUSION: Both aflibercept and ranibizumab improved VA and reduced CST in eyes with CRVO in routine clinical practice, with aflibercept showing significantly greater improvements in this comparative analysis.

Twelve-month outcomes of ranibizumab versus aflibercept for macular oedema in branch retinal vein occlusion: data from the FRB! registry.

BACKGROUND/AIMS: To compare the efficacy of ranibizumab (0.5 mg) with aflibercept (2 mg) in the treatment of cystoid macular oedema due to branch retinal vein occlusion (BRVO) over 12 months. METHODS: A multicentre, international, database observational study recruited 322 eyes initiating therapy in real-world practice over 5 years. The main outcome measure was mean change in EDTRS letter scores of visual acuity (VA). Secondary outcomes included anatomic outcomes, percentage of eyes with VA >6/12 (70 letters), number of injections and visits, time to first inactivity, switching or non-completion. RESULTS: Generalised mixed effect models demonstrated that mean (95% CI) adjusted 12-month VA changes for ranibizumab and aflibercept were similar (+10.8 (8.2 to 13.4) vs +10.9 (8.3 to 13.5) letters, respectively, p=0.59). The mean adjusted change in central subfield thickness (CST) was greater for aflibercept than ranibizumab (-170 (-153 to -187) µm vs -147 (-130 to -164) µm, respectively, p=0.001). The overall median (Q1, Q3) of 7 (4, 8) injections and 9 (7, 11) visits was similar between treatment groups. First grading of inactivity occurred sooner with aflibercept (p=0.01). Switching was more common from ranibizumab (37 eyes, 23%) than from aflibercept (17 eyes, 11%; p=0.002). CONCLUSION: Visual outcomes at 12 months in this direct comparison of ranibizumab and aflibercept for BRVO in real-world practice were generally good and similar for the 2 drugs, despite a greater effect of aflibercept on CST and time to first grading of inactivity.

Genotype-Specific Lesion Growth Rates in Stargardt Disease.

Reported growth rates (GR) of atrophic lesions in Stargardt disease (STGD1) vary widely. In the present study, we report the longitudinal natural history of patients with confirmed biallelic ABCA4 mutations from five genotype groups: c.6079C>T, c.[2588G>C;5603A>T], c.3113C>T, c.5882G>A and c.5603A>T. Fundus autofluorescence (AF) 30° × 30° images were manually segmented for boundaries of definitely decreased autofluorescence (DDAF). The primary outcome was the effective radius GR across five genotype groups. The age of DDAF formation in each eye was calculated using the x-intercept of the DDAF effective radius against age. Discordance between age at DDAF formation and symptom onset was compared. A total of 75 eyes from 39 STGD1 patients (17 male [44%]; mean ± SD age 45 ± 19 years; range 21-86) were recruited. Patients with c.3113C>T or c.6079C>T had a significantly faster effective radius GR at 0.17 mm/year (95% CI 0.12 to 0.22; p < 0.001 and 0.14 to 0.21; p < 0.001) respectively, as compared to those patients harbouring c.5882G>A at 0.06 mm/year (95% CI 0.03-0.09), respectively. Future clinical trial design should consider the effect of genotype on the effective radius GR and the timing of DDAF formation relative to symptom onset.

Incidence of Newly Registered Blindness From Age-Related Macular Degeneration in Australia Over a 21-Year Period: 1996-2016.

PURPOSE: Report the age-standardized annual incidence of blindness registration due to age-related macular degeneration (AMD) in Australia in patients aged 50 years and older. Frequencies of photodynamic therapy (PDT) and intravitreal therapy (IVT) were examined. DESIGN: Retrospective observational study. SETTING: Registry of the Association for the Blind of Western Australia with best-corrected visual acuity worse than 20/200 in the better-seeing eye. PARTICIPANTS: Registering as blind aged 50 years or over. MEASURES: Annual age-standardized incidence of blindness over 3 time periods: 1996-2001 (pre-PDT), 2002-2007 (PDT era) and 2008-2016 (IVT era). The rates of PDT and IVT usage were assessed. RESULTS: Age-standardized annual incidence of blindness rose during the PDT era, reaching 72.5 cases per 100,000 person-years in 2004. The incidence declined from 2007 onwards, reaching 8.2 cases per 100,000 person-years in 2016 (IVT era). The age at AMD blindness registration increased from 82.7 to 84.9 and 83.7 to 86.0 years from the PDT era to the IVT era in both male and females (P < 0.001) respectively. Over the same time period, PDT usage increased in 2002 and declined in 2006, whereas IVT usage increased from 2009 by 3745 per year. CONCLUSION: The increase in new blindness registrations due to AMD coincided with public funding of verteporfin for PDT, whereas the subsequent decline occurred when bevacizumab was used off-label and ranibizumab and aflibercept were publicly funded. An understanding of the effect of retinal therapy on public health measures may inform improvements in the allocation of limited resources.

CLASSIFYING ABCA4 MUTATION SEVERITY USING AGE-DEPENDENT ULTRA-WIDEFIELD FUNDUS AUTOFLUORESCENCE-DERIVED TOTAL LESION SIZE.

PURPOSE: To establish a mutation-specific age-dependent ultra-widefield fundus autofluorescence (UWF-FAF) trajectory in a large Stargardt disease (STGD1) cohort using total lesion size (TLS) and to develop a clinical method for variant classification. METHODS: A retrospective study of patients with biallelic ABCA4 mutations that were evaluated with UWF-FAF. Boundaries of TLS, defined by stippled hyper/hypoautofluorescence, were outlined manually. Pathogenicity was assessed according to ACMG/AMP criteria, and mutation severities were classified based on the current literature. Age-dependent trajectories in TLS were examined in patients with nullizygous, mild, and intermediate mutations. Mutations of uncertain severities were classified using a clinical criterion based on age of symptom onset and TLS. RESULTS: Eighty-one patients with STGD1 (mean age = 42 ± 20 years and mean visual acuity = 20/200) were recruited from 65 unrelated families. Patients with biallelic null/severe variants (n = 6) demonstrated an increase in TLS during their second decade reaching a mean ± SD of 796 ± 29 mm2 by age 40. Those harboring mild mutations c.5882G>A or c.5603A>T had lesions confined to the posterior pole with a mean ± SD TLS of 30 ± 39 mm2. Intermediate mutations c.6079C>T or c.[2588G>C;5603A>T] in trans with a null/severe mutation had a mean ± SD TLS of 397 ± 29 mm2. Thirty-two mutations were predicted to cause severe (n = 22), intermediate (n = 6), and mild (n = 5) impairment of ABCA4 function based on age of symptom onset and TLS. CONCLUSION: Age-dependent TLS showed unique ABCA4 mutation-specific trajectories. Our novel clinical criterion using age of symptom onset and TLS to segregate ABCA4 mutations into three severity groups requires further molecular studies to confirm its validity.

Inherited retinal diseases are the most common cause of blindness in the working-age population in Australia.

Background: This study examined the frequency of inherited retinal diseases (IRDs) as the reason for blindness registrations over the last two decades and the demographic and clinical phenotypes of inherited retinal disease (IRD)-related registrations.Materials and methods: Retrospective, observational study of individuals registered with a state-wide blind and vision-impaired registry. Low-vision or blindness-only (≤20/200 or ≤20°) certificates issued to children (0-15 years), working-age (16-64 years) and older-age (65 and older) adults were assessed. Sex and age distributions were examined for the top 20 reasons for certification. Demographic and clinical features of specific phenotypes of IRDs listed in the registry were examined.Results: Amongst 11824 low-vision certificates issued between July 1995 and January 2017, 679 (5.7%) listed an IRD as the reason for registration. In individuals with blindness-only certification (N=4919), IRDs was the second most common diagnosis (8.3%), overtaking glaucoma (8.1%) and diabetic retinopathy (5.4%). IRD was the second most common reason for low-vision certification amongst children (11.6%) and the most common reason amongst working-age population (23.3%). The mean±SD age for IRD-related blindness-only certification was 46±20 years. The top three phenotypes of IRD-related low-vision certification were non-syndromic retinitis pigmentosa (54%), Stargardt disease (12%) and macular dystrophy (8%).Conclusion: Our findings of IRDs as a common cause of blindness in all ages justify continued funding for providing low-vision services and developing treatments for these conditions.